GB2151624A

GB2151624A - Imidazo1 2-cpyrimidine

Info

Publication number: GB2151624A
Application number: GB08432343A
Authority: GB
Inventors: Wilfred Roger Tully
Original assignee: Roussel Laboratories Ltd
Current assignee: Roussel Laboratories Ltd
Priority date: 1983-12-22
Filing date: 1984-12-21
Publication date: 1985-07-24
Also published as: ES8701760A1; FI845102A0; PT79732A; FI78099B; GB2151624B; ZA849553B; FI78099C; NZ210715A; HU192653B; ATE42292T1; AU565745B2; ES550003A0; GB8432343D0; EP0147312A2; EP0147312A3; CA1233175A; DE3477782D1; JPS60169479A; ES8605521A1; DK605484D0

Abstract

Novel imidazo[1,2-c]pyrimidines of the formula <IMAGE> I wherein R is an aryl of 6 to 12 carbon atoms, R1 is selected from the group consisting of hydrogen and alkyl, alkoxy and alkylthio of 1 to 5 carbon atoms when R2 and R3 together form a carbon-nitrogen bond or R1 and R2 together are =0 when R3 is selected from the group consisting of hydrogen, alkyl of 1 to 5 carbon atoms and alkenyl of 2 to 5 carbon atoms, R4 is selected from the group consisting of alkoxy and alkylthio of 1 to 5 carbon atoms, R5 is selected from the group consisting of hydrogen and alkyl of 1 to 5 carbon atoms and their non-toxic, pharmaceutically acceptable acid addition salts having anxiolytic properties.

Description

1 GB 2 151 624A 1 SPECIFICATION lmidazo[1,2-c]pyrimidines The present

invention relates to new imidazo[1,2-c]pyrimidines and salts thereof, to processes 5 for the preparation of such compounds and to their use as medicaments.

Accordingly, in a first aspect, the invention provides compounds of the formula 1 R 5 CO -R R 3 R2 R1 (I) (wherein R represents a C6-12 aryl group; R, represents a hydrogen atom or a C,_5 alkyl, C,-, alkoxy or C,-, alkylthio group and R2 and R, together represent a carbon-nitrogen bond, or R, and R2 together represent a ketonic oxygen atom and R3 represents a hydrogen atom or a C,-, alkyl or a C2-, alkenyl group; R, represents a C,-, alkoxy or alkylthio group; and R, represents a hydrogen atom or a C,, alkyl group) and acid addition salts thereof.

In the above general formula 1 and throughout this specification:

the term "C,-, alkyl group- includes, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl or pentyl group; the term "C,-, alkoxy group- includes, for example, a methoxy, ethoxy, propoxy, isopropoxy, 30 butoxy, isobutoxy, tert.butoxy or pentoxy group; the term "C,-, alkylthio group- includes, for example, a methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobuty[thio, tert. butylthio or pentylthio group; the term---C,-,2 aryl group- includes, for example, a phenyl or naphthyl group; and the term "C,-, alkenyl group- includes, for example, an allyl group.

The acid addition salts may be formed with inorganic or organic acids; they may, for example, be salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, propionic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic acids, alkanesulphonic acids (eg methanesulphonic acid) and aryisulphonic acids (eg benzenesul- phonic acid).

Amongst the compounds of the invention may be mentioned those of formula 1 and acid addition salts thereof, in which R represents a phenyl group and IR, IR, IR, R, and R, are as defined above, and in particular those in which R represents a phenyl group and R, represents a methoxy group or a methylthio group.

Most preferred amongst the compounds of the invention are those wherein R, and R, together 45 represent a carbon-nitrogen bond or R, represents a C,-, alkyl or C,-, alkenyl group, R, represents a methoxy or methylthio group and R represents a phenyl group, and especially:

2-berizoyl-6 -ethyl- 7-m ethoxyi m i dazo[ 1, 2-c]pyri m i d i n- 5-one, 2-benzoyi-7-methoxy-6-propylimidazo[1,2-c]-pyrimidin-5-one, (5-ethyi-7-methoxyi m idazo[ 1, 2-c]pyri mid in-2-yi)phenyl methanone, (7-methoxy-5-methylimidazo[1,2-c]pyrimidin-2-yi)phenyimethanone, 6-aiiyi-2-benzoyi-7-methoxyimidazo[1,2-c]-pyrimidin-5-one, {7-methoxy-5-(methyithio)i m idazo[ 1, 2-c]pyri midi n-2-yI} phenyl methanone, 2-benzoyi-6-ethyi-7-(methylthio) imidazo[1,2-c]-pyrimidin-5-one, and acid addition salts thereof.

The compounds according to the invention may, for example, be prepared by cyclising a compound of formula V 2 GB 2 151 624A 2 R RL R$1 (V) CH: - co - co - R [wherein R'. represents a hydrogen atom or a C,, alkyl, C,, alkylthio or C,, alkoxy group, X(-- represents an anion (eg a halide ion) and R, R4 and R. are as defined above] to give a compound of formula 1 in which R. represents a hydrogen atom or together with R, represents a carbon- nitrogen bond, followed, if desired, by reaction of a compound of formula 1 in which R, 15 represents a hydrogen atom initially obtained with a compound of formula IV A-R', (IV) [wherein A represent a halogen atom (eg an iodine atom) and R, represents a C,, alkyl or C,-, alkenyl group] to give a compound of formula 1 in which R, represents a C,, alkyl or C,-, 20 alkenyl group.

T:i- above process constitutes a further feature of the present invention.

A compound of formula 1 obtained by the above process may, if desired, subsequently be converted into an acid addition salt. Conversely, an acid addition salt of a compound of formula 1 may if desired subsequently be converted into a compound of formula 1.

In formula V above, the anion X - + is preferably a bromide ion.

The reaction of a compound of formula 1 in which R, represents a hydrogen atom with a compound of formula]V may be carried out in the presence of a solvent (such as, for example, dimethylformamide) using, for example, an alkyl or alkenyl iodide of formula IV in the presence of a base such as, for example, sodium hydride.

The process conditions under which the cyclisation of the compound of formula V is effected may be varied depending on the product desired. In general, cyclisation can conveniently be effected by refluxing the compound of formula V in a suitable solvent, e. g. a lower alkanol.

According to one embodiment of the process according to the invention, a compound of formula V in which R,' represents a C,-, alkoxy group may be cyclised at a temperature greater 35 than 7WC, e.g. by refluxing in ethanol, to yield a compound of formula 1 in which R, and R, together represent a ketonic oxygen atom. Where a compound of formula 1 in which R, represents a C,-, alkoxy group is required, a compound of formula V in which R,' represents a C,, alkoxy group may be cyclised at a lower temperature, e.g. by refluxing in methanol, to yield the desired product. Such a process constitutes a further embodiment of the process according 40 to the invention.

According to a still further embodiment of the process according to the invention. compound's of formula 1 in which R, represents a hydrogen atom or a C,-, alkyl or C,- , alkylthio group may be obtained by cyclisation of a compound of formula V in which R,' represents a hydrogen atom or a C,-, alkyl or C-, alkylthio group, e.g. by refluxing the compound of formula V in ethanol. 45 Compounds of formula V may be prepared by reaction of a compound of formula 11 R 5 R4 1 (II) R11 55 (wherein R',, R, and R, are as defined above) with a compound of formula Ill X-CH,-CO-CO-R (111) [wherein R is as defined above and X represents an atom or group capable of elimination to form the anion X(:3. (eg a halogen atom, preferably a bromine atom)]. The reaction is preferably carried out in the presence of an organic solvent such as, for example, tetrahydrofu65 ran, ethyl ether or dimethoxyethane.

3 GB 2 151 624A 3 When they are not known per se, the compounds of formula 11 may, for example, be prepared by using methods analagous to those described in Chem. Pharm. Bull., 1976, 24(3), 507; JACS, 1951, 73, 106; Chem. Ber., 1942, 75, 755; and Chem. Pharm. Bull., 1970, 18, 1385.

The reaction described above for the initial preparation of a compound of formula V can, if 5 desired, be carried out in such a way as to lead to the formation of a compound of formula 1 without intermediate isolation of the compound of formula V.

The above cyclisation reactions of the compounds of formula V will lead in some cases to the formation of the compounds of formula 1 as free bases and in some cases to the formation of acid addition salts of the compounds of formula 1 (eg with the acid HX), depending on the 10 basicity of the compounds formed. In cases where an acid addition salt is formed initially, the free base of formula 1 may be obtained from the acid addition salt, if desired without previous isolation, by treatment with a base such as, for example, an alkali metal hydroxide, bicarbonate or carbonate, eg potassium carbonate or sodium bicarbonate. A base of formula 1 may be converted into an acid addition salt by reacting the compound of formula 1 with an inorganic or organic acid, preferably in substantially stoichiometric proportions. The salts can be prepared if desired without intermediate isolation of the compound of formula 1.

The compounds of formula Ill wherein X represents a halogen atom may, for example, be prepared by halogenating a compound of formula CH,-CO-CO-R (wherein R is as hereinbefore defined) in the manner described in Heiv. Chim. Acta, 1946, 29, 1247.

The compounds of formula CH,-CO-CO-R may, for example, be prepared by bromination of a compound of formula CH,-CH,CO-R followed by reaction with sodium methoxide, to give a compound of formula OCH, 1 CH3-C-CO-R 1 OCH, which is subsequently reacted with acid (eg hydrochloric acid) to give the desired compound of formula CH,-CO-CO-R The compounds of the present invention have very interesting pharmacological properties. They are particularly notable for their anxiolytic properties, which are illustrated by test results given hereinafter. These properties suggest the use of the compounds of formula 1 and their pharmaceutical ly acceptable salts as drugs, and accordingly the present invention provides, in a further aspect, compounds of formula 1 and pharmaceutical ly acceptable acid addition salts thereof, for use in therapy, in particular anxiolytic therapy, of the human or animal body. 50 Preferred in this connection are compounds of formula 1 failing within the preferred definitions 50 already given above and the specific compounds already listed, and pharmaceutically acceptable salts of such compounds. Compounds of formula 1 may thus find use for example in the treatment of anxiety states such as chronic anxiety, accompanied by agitation, irritability or aggression, anxiety with insomnia and muscular tension and distress.

The invention accordingly further provides pharmaceutical compositions containing, as active ingredient, at least one compound of formula 1 or a pharmaceutically acceptable salt thereof.

For pharmaceutical administration the compounds of formula 1 and their pharmaceutical ly acceptable salts may for example be incorporated in compositions for administration via the digestive or parenteral routes.

The pharmaceutical compositions may for example be solids or liquids, presented in conventional form, for example tablets (including plain or coated tablets), capsules, gelatin capsules, granules, suppositories, and injectable preparations, prepared in conventional manner.

The active ingredients(s) may be used in conjunction with excipients customarily employed in pharmaceutical compositions for example talc, gum arabic, lactose, starch, magnesium stearate, 65 4 GB 2 151 624A cocoa butter, aqueous or non-aqueous vehicles, animal or vegetable fats, paraffin derivatives, glycols, and various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adult human treatment may contain from 0. 1 to 100 mg, preferably from 0. 1 to 20 mg of active ingredient. The daily dosage will vary depending on the product employed, the subject to be treated and the condition, but will generally be in the range 0. 1 to 200 mg per day for oral administration for adult human treatment.

The following non-limiting examples illustrate the invention.

Preparation of the starting materials Example A 3-Bromo- 1-phenylpropane1,2-dione 1. 1-Phenylpropane-1,2-dione Propiophenone (6.0 kg, 44.78 mole) and anhydrous aluminium chloride (92 g) were added to 15 ether (6 1) followed by bromine (17.2 kg, 107.5 mole) at a rate to maintain a gentle reflux. When the addition was complete (approximately 6 hours) the mixture was heated to reflux overnight, then the solvent was removed under vacuum to leave a lachrymatory dark red/orange oil. The oil was slowly added to a solution of sodium (2.81 kg, 122.2 mole) in methanol (45 1) while maintaining the temperature below 2WC. When the addition was complete conc. hydrochloric acid (12.5 1) was added and the mixture stirred at room temperature for 1 hour. The precipitate was filtered off then the filtrate reduced in volume to approximately 25 1 by distillation of the methanol. The residue was partitioned between chloroform (10 1) and water (10 1) then the organic phase was separated and the aqueous phase extracted with chloroform (2 X 5 1). The combined chloroform solutions were dried (sodium sulphate) then the solvent evaporated and the residue fractionally distilled under vacuum through a 30 cm Fenske column to give 1 -phenylpropane-1,2-dione (b.p. 77-85'C) at 1 -2 mm. Yield 5.7 kg (86%).

2. 3-Bromo-l-phenylpropane-1,2-dione 1 -Phenyl propa ne- 1, 2-d ione (5.32 kg-98.6% by G.C. equivalent to 5.24 kg, 35.4 mole) was dissolved in chloroform (36 1) and heated to 5WC. A solution of bromine (5.66 kg, 35.4 mole) in chloroform (8 1) was added slowly to maintain a gentle reflux and immediate decolourisation of the bromine (approximately 6 hours). The solution was cooled to room temperature overnight then washed with saturated sodium bicarbonate solution (20 1) and water 35 (20 1) and dried (sodium sulphate). The solvent was removed under vacuum to leave a green/yellow oil which was used directly for subsequent reactions after estimation of its purity (approximately 7 5%) by G.C. or N. M. R. Yield 8. 2 kg (100%) Preparation of the end products EXAMPLE 1

2-Benzoyl-7-methoxyimidazo[1,2-clpyrimidin-5-one A stirred solution of 2,6-dimethoxy-4-pyrimidinamine (1 Og) in dry tetrahydrofuran (25 mi) was treated with a solution of 3-bromo-1 -phenyl- 1,2-propanedione (70%, 21 9) in dry diethyl ether (50 m[). After stirring overnight, diethyl ether (20 mi) was added, the mixture chilled and the 45 crystalline pyrimidinium salt filtered off (16.7 g).

A solution of the salt (10 g) in ethanol (30 mi) was refluxed for 2 hours under nitrogen, cooled, diluted with diethyl ether (30 mi) and chilled. 2-Benzoyi-7- methoxyimidazo[1,2c]pyrimi- din-5-one (4.4 9) was filtered off as a yellow crystalline solid, m.p. 208-1 O'C. A further quantity (1.4 g) was obtained by chromatographing the residue from evaporation of the filtrate 50 in ethyl acetate on silica.

EXAMPLE 2

2-Benzoyl-6-ethyl-7-methoxyimidazo[1,2-c]pyrimidin-5-one.

A stirred solution of 2-benzoyi-7-methoxyimidazo-[ 1 2-c]pyri mid in-5one (11 9) in dry dime thylformamide (33 mi) was treated with sodium hydride (80%, 1.27 g) and stirred for a further hour. lodoethane (8 9) was added dropwise over 10 minutes and stirring continued for 2 hours after which the mixture was poured onto iced water to precipitate 2benzoyi-6-ethyl-7 methoxyimidazo[1,2-c]pyrimidin-5-one (2.3 9) as a yellow crystalline solid, m. p. 159-60'C.

EXAMPLE 3

2-Benzoyi-7-methoxy-6-propytimidazo[1,2-clpyrimidin-5-one.

Using a method similar to that used in Example 2 but starting from the 2benzoyl-7 methoxyimidazo[1,2-c]-pyrimidin-5-one and iodopropane, the 2-benzoyl-7- methoxy-6-propylimi- dazo[1,2-c]pyrimidin-5-one was prepared. Spectral, yield and melting point data are given in 65 GB 2 151 624A 5 Table 1.

EXAMPLE 4 (7-Methoxy.-5-methylimidazo[1,2-clpyrimidin-2-yl)phenyimethanone.

A stirred solution of 6-methoxy-2-methyi-4-pyrimidinamine (2.1 9) in dry tetrahydrofuran was treated with a solution of 3-bromo- 1 -phenyl- 1, 2-propa ned ion e (70 %, 5.4 9) in dry diethyl ether (5 mi). After stiring overnight the mixture was chilled and the precipitated salt filtered off. A suspension of the salt in dry ethanol was refluxed for 1.5 hours, chilled, and solid material filtered off.

The solid was shaken with a mixture of chloroform and aqueous sodium bicarbonate. The 10 organic layer was evaporated to dryness under reduced pressure and the residue chromato graphed in ethyl acetate on silica to give (7-methoxy-5-methylimidazo[1,2- c]pyrimidin-2-yl)phe- nyimethanone (2.7 g) as a yellow crystalline solid, m. p. 165-7'C.

EXAMPLES 5 TO 15 Using methods similar to those used in Examples 1, 2 or 4 (designated methods A, B and C respectively in Table 1 below) but starting from the corresponding compounds of formula 11, or from the corresponding compounds of formula 1, wherein R3 represents a hydrogen atom, the compounds of Examples 5 to 9 and 12 to 15 were prepared. The compound of Example 10 was prepared by a method (denoted A in Table 1 below) analogous to that of Example 1 but 20 using methanol rather than ethanol iin the cyclisation step. The compound of Example 11 was obtained as a by-product of Example 2 but could more efficiently be prepared by method A.

Spectral, yield melting point and analytical data are also given in table 1.

EXAMPLE 5:

(5-ethyl- 7-m eth oxy i m idazo[ 1, 2-c]pyri midi n-2-y1)phenyl meth a none.

EXAMPLE 6:

2-benzoyi-7-ethoxyimidazo[1,2-c]pyrimidin-5-one.

EXAMPLE 7:

2-benzoyl- 7 -methoxy-6 -methyl i m idazo [ 1, 2-c]-pyrimidin-5-one.

EXAMPLE 8:

(7-methoxy- 5,8-d i methyl i m i d azo[ 1, 2-c-pyri midi n-2-y1)phenyl meth a none.

EXAMPLE 9:

6-al lyi-2-benzoy]-7-methoxyi midazo[ 1, 2-c]-pyri mid in-5-one.

EXAMPLE 10:

(5,7-d i methoxyi m idazo[ 1, 2-c]pyri mid in-2-y1)phenyl methanone.

EXAMPLE 11:

(5-ethoxy-7-methoxyimidazo[1,2-c]pyrimidin-2-yi)phenyimethanone.

EXAMPLE 12:

17-methoxy-5-(methytth io)i m idazo[ 1, 2-cl-pyri midi n-2-y1} phenyl methanone EXAMPLE 13:

{5,7-bis(methylthio)imidazo[1,2-c]pyrimidin-2-yi} phenyl methanone.

EXAMPLE 14:

2-benzoyi-6-ethyi-7-(methy[thio)imidazo-[1,2-c]pyrimidin-5-one.

EXAMPLE 15: 6-a 1 lyi-2-benzoyi-7-(methyith io)i midazo-[ 1, 2-c]pyri midi n-5-one. 45 6 GB 2 151 624 TABLE I

Ex. R R 1 R2 R 3 R 4 R 5 Method Yield 1 Ph =0 H CH 3 0 H A 64 2 Ph =0 c 2 H 5 CH 3 0 H B 19 3 Ph =0 c 3 H 7 CH 3 0 H B 18 4 Ph CH 3 CH 3 0 H c 67 Ph C 2 H 5 CH 3 0 H c 45 6 Ph =0 H c 2 H 5 0 H A 20 7 Ph --0 CH 3 CH 3 0 H B 40 8 Ph CH 3 CH 3 0 CH 3 c 44 9 Ph =0 CH 2 =CHCH 2 CH 3 0 H B 26 Ph CH 3 0 CH 3 0 H A 71 11 Ph C2 H 5 0 CH 3 0 H B 0.3 12 Ph CH 3 S CH 3 0 H c 29 13 Ph CH 3 S CH 3 S H c 25 14 Ph --0 c 2 H 5 CH 3 S H B 47 Ph =O CH 2 =CH-CH 2-CH 3 S H B 52 TABLE I (Contld), 35 Ex. IR cm- 1 (KBr disc) M.P. Formula M.Wt.

1 1640,1670,1650,1610 208-100C c 14 H 11 N 3 0 3 269.3 2 1700,1640,1600,1580 159-600C c 16 H 15 N 3 0 3 297.3 3 1710,1630,1600,1580 106-70C c 17 H 17 N 3 0 3 311.3 4 1645,1635,1595,1575 165-70C c 15 H 13 N 3 0 2 267.3 1640,1600,1560,1500 152-30C c 16 H is N 3 0 2 281.3 6 1730,1670,1650,1600 218-200C c 15 H 13 N 3 0 3 283.3 7 1710,1625,1600,1570 187-90C c 15 H 13 N 3 0 3 283.3 8 1640,1630,1600,1580 185-70C c 16 H 15 N 3 0 2 281.3 9 1710,1660,1630,1590 139-410C c 17 H 15 N 3 0 3 309.3 1650,1630,1600r1570 141-30C c 15 H 13 N 3 0 3 283.3 11 1660r1640,1600,1590 116-80C c 16 H 15 N 3 0 3 297.3 12 1640,1620r1515,1460 149-500C c 15 H 13 N 3 0 2 S 299.35 13 1640r1600r1580,1520 154-50C c is H 13 N 3 OS 2 315.4 14 1680r1635,1600,1580 152-40C c 16 H 15 N 3 0 2 S 313.4 1690r1635,1595 1610C c 17 H 15 N 3 0 2 S 325.4 7 GB 2 151 624A 7 TABLE I (Cont'd) Ex.

2 3 4 6 7 8 9 11 12 13 14 c H Theory/Found N S 62.45 " />62. 19 64.64 A64. 66 65.58 /65.59 67.41 /6 7. 2 68.31 768.19 63.60 763.58 63.60 763.47 68.31 768.38 66.01 765.82 63.60 " ;'6 3. 7 3 64.64 764.55 60.19 760.18 4.12 4. 15 5.09 75.09 51 75.77 4.90 4. 98 5.37 75.44 4.62 74.58 4.62 74.70 i 37 K, 16 4.89 74.97 4.62 4. 63 097 5.08 4.38 / 4. 43 4.15 74.20 4.82 74.86 4.65 74.73 15.16 is. 38 14. 13 714.15 13.50 713.38 15.72 /15. 6 5 14.94 Y14. 91 14.83 714.56 14.68 714.87 14. 4 714.96 13.58 713.56 14.83 l4. 9 0 14.13 1K4 19 04 714.06 13.32 713.32 13.41 l3. 3 8.93 712.86 i 1 57.12 57.28 61.32 761.70 62.75 62. 77 107 /k /0. 6 3 20.33 20.06 10.23;>110,. 2 9 9.85 79.77 - --- 1 8 GB 2 151 624A 8 EXAMPLE 16

Tablets were prepared according to the formulation:

-compound of Example 2 20 mg excipient q.s. for one tablet up to 150 mg (Details of the excipient: lactose, starch talc, magnesium stearate).

EXAMPLE 17

Tablets were prepared according to the formulation:

----compound of Example 5 20 mg xcipient q.s. for one tablet up to 150 mg (Details of the excipient: lactose, starch, talc, magnesium stearate).

Biochemical and Pharmacological Activity 1) Biochemical Activity The affinity of the compounds for the benzodiazepine receptor was assessed using the 20 radioligand [3 H]flunitrazepam and modifications of the original radioreceptor binding method of Squires and Braestrup (Nature, 1977, 266, 732). The values given in Table 11 are nanomolar concentrations of test drug which inhibited the specific binding of 0. 6nM[IH]flunitrazepam to rat forebrain membrane preparations by 50% (IC,, nM).

2) Pharmacological Activity Screening for anxiolytic activity was carried out by modifications of the conflict method of Geller and Seifter (Psychopharmacologia, 1960, 1, 482). The values given in Table 11 are the minimum effective doses at which there was an observed increase in shocks above control (MED mg/kg po).

Table II

EXAMPLE RECEPTOR BINDING F (IC 50 nM) GELLER CONFLICT (MED mg/kg po) 2 2000 2 3 1000 10 4 520 50 215 10 9 500 5 1000 10 11 890 - 12 126 5 13 18 50 14 140 5 120 -

Claims

CLAIMS 1. Compounds of the formula 1

9 GB 2 151 624A 9 5 R4 CO -R R 3 N R2 R1 (I) (wherein R represents a Cl-12 aryl group; R, represents a hydrogen atom or a C,, alkyl, C,, alkoxy or C,-, alkylthio group and R2 and R, together represent a carbon-nitrogen bond, or R, and R2 together represent a ketonic oxygen 15 atom and R, represents a hydrogen atom or a C,-, alkyl or a C2-1 alkenyl group; R, represents a C,-, alkoxy or alkylthio group; and R, represents a hydrogen atom or a C,-, alkyl group) and acid addition salts thereof.
2. Compounds as claimed in claim 1 wherein R represents a phenyl group.
3. Compounds as claimed in claim 2 wherein R, represents a methoxy group or a methylthio20 group.
4. Compounds as claimed in claim 1 wherein R, represents a methoxy or methylthio group, R represents a phenyl group and R2 and R. together represent a carbon-nitrogen bond or R3 represents a C,-, alkyl or C2-, alkenyl group.
5. 2-Benzoyl-6-ethyl-7-methoxyimidazo[1,2-c]pyrimidin-5-one and acid addition salts thereof. 25
6. 2-Benzoyl-7-methoxy-6-propylimidazo[1,2-elpyrimidin-5-one and acid addition salts thereof.
7. (5- Ethyl-7-methoxyi m idazo[ 1, 2-c]pyri midi n-2-yl)p henyl metha none and acid addition salts thereof.
8. (7-Methoxy-5-methylimidazo[1,2-c]pyrimidin-2-yi)phenyimethanone and acid addition 30 salts thereof.
9. 6-Ally]-2-benzoyl-7-methoxyimidazo[1,2-c]-pyrimidin-5-one and acid addition salts thereof.
10. (7-Methoxy-5-(methytthio)imidazo[1,2-c]pyrimidin-2-yi)phenyimethanone and acid addition salts thereof.
11. 2-Benzoyl-6-ethyl-7-(methyithio)imidazo[1,2-c]-pyrimidin-5-one and acid addition salts 35 thereof.
12. Compounds as claimed in claim 1 as herein specifically disclosed.
13. A process for the preparation of compounds as claimed in claim 1 which comprises cyclising a compound of formula V 40 R4 H X 2 (V) 45 CH2 - CO co - R R' 1 [wherein R,' represents a hydrogen atom or a C,-, alkyl, C,-, alkylthio or C1-5 alkoxy group; 50 X(, -t represents an anion; and R, R, and R, are as defined in claim 1] to give a compound of formula 1 in which R, represents a hydrogen atom or together with R, represents a carbon nitrogen bond followed, if desired, by reaction of a compound of formula 1 in which R, represents a hydrogen atom initially obtained with a compound of formula IV A-R', (IV) [wherein A represent a halogen atom and W, represents a Cl-5 alkyl or C,-, alkenyl group] to give a compound of formula 1 in which R3 represents a C,-, alkyl or C,-, alkenyl group: with optional subsequent conversion of a compound of formula 1 into an acid addition salt thereof or 60 of an acid addition salt of a compound of formula 1 into the free base of formula 1.
14. A process as claimed in claim 13 wherein a compound of formula V in which X represents a bromide ion is used.
15. A process as claimed in claim 13 or claim 14 wherein a compound of formula V in which W, represents a C,-, alkoxy group is cyclised to yield a compound of formula 1 in which 65 GB 2 151 624A 10 R, and R2 together represent a ketonic oxygen atom.
16. A process as claimed in claim 15 wherein cyclisation of the compound of formula V is effected by refluxing the compound of formula V in ethanol.
17. A process as claimed in claim 13 or claim 14 wherein a compound of formula V in which R,' represents a C,, alkoxy group is cyclised to yield a compound of formula 1 in which 5 R, represents a C,-, alkoxy group.
18. A process as claimed in claim 17 wherein cyclisation of the compound of formula V is effected by refluxing the compound of formula V in methanol.
19. A process as claimed in claim 13 or claim 14 wherein a compound of formula V in which R,' represents a hydrogen atom or a C,-, alkyl or C,-, alkylthio group is cyclised to yield a 10 compound of formula 1 in which R, is as defined for IR,'.
20. A process as claimed in claim 19 wherein cyclisation of the compound of formula V is effected by refluxing the compound of formula V in ethanol.
21. A process as claimed in any one of claims 13 to 16 where the reaction of a compound of formula 1 in which R, represents a hydrogen atom with a compound of formula IV is effected 15 in the presence of dimethylformamide as solvent.
22. A process as claimed in any one of claims 13 to 16 and 21 wherein a compound of formula IV in which A represents an iodine atom is used.
23. A process as claimed in any one of claims 13 to 22 wherein the compound of formula V is obtained by reaction of a compound of formula 11 R 5 1 (M) R11 (wherein R,' is as defined in claim 13 and R, and R, are as defined in claim 1) with a compound of formula X-CH2-CO-CO-R (111) (wherein R is as defined in claim 1 and X represents an atom or group capable of elimination to form the anion Xe).
24. A process as claimed in claim 23 wherein a compound of formula Ill in which X represents a bromine atom is used.
25. A process as claimed in claim 23 or claim 24 wherein the reaction of the compound of formula 11 with the compound of formula Ill is carried out in the presence of tetrahydrofuran, ethyl ether or dimethoxyethane as solvent.
26. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.
27. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 15.
28. Compounds of formula 1, as defined in claim 1, and acid addition salts thereof whenever prepared by a process as claimed in any one of claims 13 to 27.
29. Compounds of formula 1, as defined in claim 1, and pharmaceutically acceptable acid 50 addition salts thereof for use in therapy.
30. Pharmaceutical compositions comprising as active ingredient a compound of formula 1, as defined in claim 1, or pharmaceutically acceptable acid addition salt thereof in association with a carrier or excipient.
31. Compositions as claimed in claim 30 in the form of dosage units, each dosage unit 55 containing from 0. 1 to 100 mg of active ingredient.
32. Compositions as claimed in claim 31 wherein each dosage unit contains from 0. 1 to 20 mg of active ingredient.
33. Compositions as claimed in any one of claims 30 to 32 wherein the reactive ingredient is a compound as claimed in any one of claims 2 to 11.
34. Pharmaceutical compositions substantially as herein described.

35, h Pharmaceutical compositions substantially as herein described in Example 16 or Example 17.

11 GB 2 151 624A 11 Printed in the United Kingdom for Her Majesty's Stationery Office, Dd 8818935, 1985, 4235. Published at The Patent Office, 25 Southampton Buildings, London, WC2A 'I AY, from which copies may be obtained.